Many applications require the controlled mixing and/or delivery of fluid eluents, liquid chromatography ("LC") for example. In LC, a flowing stream of liquid solvent in a mobile phase carries a liquid sample containing components to be analyzed. A precision pump mechanism causes the liquid solvent to pass through a chromatography column typically packed with ion exchange particles in a stationary phase. While passing through the column, components within the liquid sample are differentially adsorbed and desorbed from the stationary phase. These individual components then elute from the column at different times and are separately detected and quantified as they flow through a detector. In this fashion, analytical information is provided as to the constituents present in the liquid sample.
Even more effective separations result from high performance liquid chromatography systems ("HPLC"), wherein mixtures of solvents are used as the mobile phase. When the components of the mixture are held constant, an isocratic mode results. By contrast, gradient chromatography results when the composition of the liquid changes over time while being pumped to the column, for example, a composition going from 100% water to 100%, methanol.
FIG. 1 depicts a generic liquid chromatography system that may be operated in an HPLC mode, wherein differential analysis may be provided It is the purpose of precision pump mechanism 10 to deliver a liquid solvent via an output port 12 at a constant flowrate to a column 14 or other downstream analytical apparatus. In the HPLC mode, there are at least two sources of liquid input, 16A, 16B, each of which may contain different constituents.
In FIG. 1, liquid input sources 16A, 16B are coupled to a proportioning valve 17 whose operation is controlled by the digital control system 28. Through a "T-connector", valve 17 outputs liquid to inlet check valves 32A and 32B. Of course in non-differential analysis, there is a single liquid input source, e.g., 16A or 16B.
In FIG. 1, a rotary motor mechanism 18 receives an input voltage from a driver amplifier 20, and outputs rotary shaft motion in response to the input voltage. A tachometer mechanism 22 senses the rotary speed of the motor mechanism shaft 24 and provides this information as an input to the driver amplifier 20 in a closed feedback loop configuration.
As is known in the art, affixed to motor shaft 24 is a disk 26A that contains precisely located slots through which light may pass and be sensed by a sensor unit 26B that typically includes light emitting diode and detector pairs. At the motor shaft 24 rotates with speed .omega., the light sensors detect a digital pattern of light and no-light, which information is coupled to a digital control system 28. Other precision mechanisms for detecting rotary shaft speed and position could of course be used.
Digital control system 28 contains a control panel (not shown) permitting an operator to set a desired liquid flowrate at the output port 12. The output control signal from digital control system 28 is then provided as an additional input to the driver amplifier 20.
A mechanism 30 translates the rotary motion of shaft 24 to a reciprocating back-and-forth motion that is mechanically coupled to at least two piston heads (or "ends") 34A, 34B associated with surrounding cylinders (not shown). Where, as shown, two piston heads are used, they reciprocate 180.degree. out of phase. One piston intakes liquid while the other piston exhausts or outputs liquid, the intake cycle being shorter than the exhaust cycle. This two piston configuration uses a point of cross-over during which both pistons are pumping simultaneously so as to maintain system pressure without a dead zone. In this pressure mode of operation, to maintain constant system pressure and therefore constant flowrate at cross-over requires approximately halving motor speed. At cross-over, one piston is ending its exhaust cycle while the remaining piston is commencing its exhaust cycle. However, the prior art cannot accurately predict when during the system cycle motor speed should be halved to avoid significant pressure fluctuations.
In non-precision, non-proportioning applications a single reciprocating end may be used. In contrast to parallel-coupled 180.degree. out-of-phase ends, it is also known in the art to use a single motor that operates two series-coupled lead-screw heads to pump eluent to a column.
In response to the reciprocating motion provided by mechanism 30, ends 34A, 34B cause liquid from the respective liquid inputs 16A, 16B, after passing through respective unidirectional intake and exhaust check valves 32A, 32B, and 36A, 36B to be mixed at a "T"-connector proportioning valve 38. The thus-mixed liquids pass through a pressure transducer 40, through output port 12 and to the first stage of the downstream analytical apparatus, e.g., liquid chromatography column 14. As shown in FIG. 1, the output pressure measured by transducer 40 is coupled as an input to the digital control system 28 in an attempt to regulate the flowrate of the liquid exiting output port 12. Total flowrate is indirectly derived from the measured output pressure.
The real time use of output pressure data from transducer 40 to control flowrate in pump 10 is termed a pressure mode of operation. Pressure mode operation minimizes pressure ripple, and is advantageous for ion detection by conductivity or other detector. Such detection is relatively sensitive to pressure variations. However, pressure mode operation is disadvantageous where viscosity changes rapidly, or where other dynamic conditions are presented (e.g., column switching, injection, high speed operation). In the presence of such dynamically changing conditions, the lagging behind of feedback information precludes pump 10 from responding with sufficient speed to achieve the correction.
Under certain steady state conditions with normal pump speeds, even prior art pressure feedback can reduce pressure ripple effectively. However, under dynamic conditions, due to viscosity changes, high speed operation, or rapid change in system parameters as in switching columns or during an injection, the present invention reduces cross-over ripple, whereas prior art techniques cannot.
Unfortunately, prior art pump 10 cannot operate in a flow mode, wherein output flowrate is regulated without making real time use of output pressure data. Were it possible, a flow mode operation would provide superior flowrate performance in the presence of rapidly changing viscosity gradients.
The analysis application and the flowrate at output port 12 determine the liquid pressure. In practice, standard bore piston heads or ends 34A, 34B operate at 1 piston stroke every six second, which delivers approximately 1 ml/minute, whereas so-called microbore pistons deliver approximately 250 .mu.l/minute operating at the same piston stroke rate. Pressure at outlet port 12 is typically in the range 300 psi to 5,000 psi and is determined substantially by the column 14 or other apparatus downstream from the outlet port 12 of the pump 10.
In liquid chromatography, a detector (not shown) detects separated components in the eluent (solvent) passing through column 14 by outputting a peak signal. These signal peaks are then integrated as a function of time to arrive at meaningful analytical information. It is therefore important that the flowrate of the liquid at output port 12 and passing through the column 14 be a constant.
Unfortunately, prior art pump systems such as shown in FIG. 1 cannot reliably maintain a desired flowrate within an acceptable tolerance. For example, a leaky valve or piston seal will cause the pump 10 to output at less than the desired flowrate commanded by digital control system 28. Even if the valves and seals are not leaky, output flowrate can vary due to a differential change in compliance, e.g., variations in material expansion under pressure.
Further, production variations in manufacturing tolerances associated with cylinder heads, plastic or stainless steel fluid-carrying tubing, valves and other components can cause undesired deviations in the output flowrate, as can the presence of a bubble within the fluid flow path within pump 10. For example, a piston head attempting to compress liquid might in fact be compressing an air bubble, with the result that less liquid is pumped, with an attendant drop in output flowrate at port 12. Prior art control systems do not recognize such conditions, cannot distinguish between the output of each piston head, and cannot, for example, cause the higher pressure-delivering piston head to compensate for the remaining, lower-pressure, piston head.
In addition, the compliance (e.g., expandability) of the tubing, piston seals, and components comprising pump 10 may change with time, or material changes may be made, such as substituting stainless steel tubing for plastic tubing. If for whatever reason fluid-coupling components within pump 10 expand, the flowrate at outlet port 12 will be less than what digital control system 28 (and the system operator) believe to be present. Further, ambient environmental pressure or temperature, as well as changes in the liquid viscosity or compressibility can alter the output flowrate. Maintaining a constant output flowrate during chromatography using a gradient eluent is especially challenging because viscosity of the liquid mixture can rapidly vary by a factor of three.
A persistent problem in attempting to run with eluents of rapidly changing gradients is that in a conventional pressure mode system, there will always be several motor revolution cycles lagging of the necessary corrective action, while viscosity continues to change. Also, as viscosity changes, the inherent system pressure changes and the prior pressure control system undesirably changes flowrate (e.g., motor speed) to compensate for the change in pressure. Further, the prior art's reliance upon pressure parameters alone has a deleterious effect as pressure and flowrate tend to counter each other when attempting to make adjustments.
Thus, prior art systems cannot control flowrate to better than about 10% to 15% during rapid gradient change, although the error will be consistent for repeated runs. Thus, because of its relative consistency, the prior art can compensate for flowrate variation in repeated runs. Alternatively, a syringe-type lead screw system capable of only a single flowrate will be employed in the prior art during fast gradient analyses.
To recapitulate, existing pump systems operate in pressure mode, and cannot adequately compensate for variations in equipment, viscosity, pressure, compliance, temperature, the presence of air bubbles, and other variables likely to be experienced. Such systems measure and make real time use of total pressure indirectly derive flowrate. However, the total pressure under measurement will reflect leakage flow components, compliance-variable components, in addition to the actual eluent fluid flow. Simply stated, the prior art cannot distinguish or even recognize the various error components that contribute to undesired variations in output flowrate.
Thus, there is a need for a control mechanism that can control output flowrate in a precision pump despite the presence of variables including a leaky valve, an air bubble, a leaky cylinder head, variations in pressure, and compliance variations. Preferably such mechanism should permit pump system operation in flow mode, in pressure mode, and in an intelligent combination of each mode.
Such mechanism should provide acceptable flowrate control even if only one piston head is operating according to specification, wherein the correctly operating piston head compensates for the remaining piston head. In addition, such mechanism should maintain a pressure characteristic substantially free of peaks or dips over the approximate range 300 psi to 5,000 psi.
Further, such mechanism should provide experimenters with a constant fluid sample characteristic that is independent of system variables such as compliance, system fabrication tolerances, and ambient environmental changes, including transient changes. Such mechanism should reduce cross-over pressure ripple despite dynamic flow conditions, and should control flowrate even during a rapidly changing viscosity gradient experiment to within about .+-.5% or better.
The present invention provides such a control mechanism.